Pomegranate: A review of the heavenly healer’s past, present, and future

In the great Persian Empire, pomegranate (Punica granatum L.) had a wide reputation for use both as an herbal medicine and nutritious food. It was also a symbol of peace and love according to Achaemenid limestones in the great Persia. This paper aims to review the traditional uses of pomegranate in Persian and Islamic traditional medicine and have thorough and current information regarding the pharmacology and phytochemistry of this valuable plant for practical use and further research. Relevant information about P. granatum was collected from scientific publishers and databases including Elsevier, Wiley, PubMed, and Google Scholar between 1950 and 2022. The traditional knowledge was extracted from Persian and Islamic traditional textbooks. Based on traditional textbooks, pomegranate has beneficial effects on diseases related to gastrointestinal, upper and lower respiratory, visual, and reproductive systems. In addition, pomegranate and its preparations have been prescribed for treating metabolic disorders, skin problems, and wounds as well as dental protection. Preclinical and clinical evidence supports many therapeutic potentials of pomegranate in traditional medicine. Its therapeutic effects are mostly attributed to its polyphenols. The knowledge in Persian and Islamic traditional textbooks about pomegranate and its preparations can be used as a guide for further preclinical and mainly clinical studies to discover the therapeutic potential of this valuable plant.


Introduction
Pomegranate (Punica granatum L.), belonging to the Lythraceae family, is a historic fruit that is indigenous to Central Asia and may be found in places like the Middle East, Iran, and Turkmenistan to northern India (1).P. granatum (Figure 1) is a fruit-bearing shrub or a small tree that grows up to 501507 m with very diverse varieties (2).Pomegranate and its components were found to have powerful anti-oxidant, anti-inflammatory, antifungal, antibacterial, and antimicrobial effects, according to studies conducted in both in vitro and in vivo over the past few decades (1).In addition, some animal studies have shown that pomegranate may have anti-hypertensive and antiproliferative properties (3).Furthermore, pomegranate juice or extracts have been shown in multiple pre-clinical and clinical trials to have positive benefits on a number of disorders, including respiratory diseases (4), digestive problems (5), neurodegenerative diseases (6,7), metabolic disorders (8,9), cancer (3,10), osteoarthritis (11), skin problems (11), etc. Traditionally, pomegranate and its products have been used for the treatment of several health problems.In Islamic and Iranian Traditional Medicines (ITM), this valuable plant was used by traditional physicians in various preparations and diverse application forms for a wide variety of illnesses.They used different parts of the plant mainly fruit peels, fruit juice, and flowers for health problems such as skin diseases, reproductive problems, gastrointestinal disorders, infectious diseases, and respiratory problems (12)(13)(14)(15)(16)(17)(18)(19).As mentioned by ITM physicians, most of the beneficial properties of pomegranate are due to its astringent effect.Modern medicine relates this astringency to the presence of phenolic compounds including tannins.Many available pomegranate formulations in the market have been prepared according to traditional knowledge.For instance, anti-aging and cosmetic products from pomegranate are available in the market under many brand names.
Although pharmacological and clinical studies have confirmed several therapeutic effects of pomegranate products and pomegranate constituents, by looking into the uses of this plant in traditional texts, many applications can still be extracted.Nevertheless, there are still many potential applications in the traditional references that can be useful for possible formulations.To the best of our knowledge, there is no similar article discussing the traditional uses of pomegranates in Islamic and Persian medicine.Thus, in the current study, we aimed to have a comprehensive review of the application of pomegranate in ITM and compare it with modern medicine.A recent example of overlapping the traditional and modern uses of this plant is Covid-19.ITM physicians prescribed pomegranate for cough and cold, and as an antimicrobial agent.Interestingly, according to research, P. granatum and the polyphenolic components it contains may be useful against .

Phytochemistry
Depending on the cultivar, growing area, maturity, cultivation technique, climate, and storage conditions, different portions of the pomegranate have distinct chemical compositions.Although in each part of the plant, a group of specialized metabolites may dominate, the most important and biologically active constituents are polyphenols and tannins.For instance, pomegranate polyphenols particularly the anthocyanins might have significant effects against metabolic syndrome (21).Nevertheless, pomegranate includes several kinds of phytochemicals, including flavonoids, alkaloids, both condensed tannins (proanthocyanidins, are polymers formed by the condensation of flavans), and hydrolyzable tannins (ellagitannins and gallotannins) and organic acids (Table 1) (22).

Polyphenols
Pomegranate is a rich source of polyphenols including phenolic acids, anthocyanins, and hydrolyzable tannins.Several hyphenated analytical methods such as Ultra highperformance liquid chromatography-mass spectrometry (UHPLC-MS n ) have been used to examine the polyphenol profiles of different pomegranate sections (23,24).

Ellagitannins
Ellagitannins are polymeric compounds that frequently have various amounts of galloyl and hexahydroxydiphenoyl units attached to glucose.One of the metabolite categories in pomegranate that has been the subject of much research is ellagitannins.These substances, which are converted to urolithins in the digestive system, are the primary bioactive phytochemicals in pomegranate juice (22).Ellagitannins vary from gallotannins in that their galloyl groups are connected by C-C bonds.Additionally, gallotannins do not often form macrocycles, but ellagitannins do (25).

Gallotannins
Pomegranate contains some gallotannins.Gallotannins are a variant of hydrolyzable tannins.Gallotannins are polymers created when the hydroxyl group of a polyol carbohydrate, such as glucose, esterifies and bonds with gallic acid, a polyphenol monomer.For instance, 1,3,4-trigalloylglucose may be found in the leaves of pomegranates.Weak acids or bases hydrolyze this type of tannin to create glucose and phenolic acids (22,25).

Therapeutic uses of pomegranate in traditional medicine
Mohammadi et al.

Lignans
Pomegranate has been shown to contain a variety of lignans and phenylpropanoidic metabolites with estrogenic action (22,26,27).

Organic acids
Citric and malic acids are among the organic acids identified from different parts of pomegranate (22).

Anthocyanins
Pomegranate juice's crimson hue is a result of anthocyanins.Pomegranate anthocyanins such as cyanidin, pelargonidin, and delphinidin have been found to be conjugated with one or two hexose sugars (22).

Alkaloids
The three main alkaloids found in the stem and root barks of pomegranates are pelletierine, pseudopelletierine, and N-methylpelletierine (29).Sedridine, 2-(2′-hydroxypropyl)-∆ 1 pip e r i d e i n e , 2 -( 2 ′ -pro p e ny l ) -∆ 1 pip e r i d e i n e , norpseudopelletierine, and the pyrrolidine alkaloids (with a five-membered N-containing ring) hygrine and norhygrine have also been found in root barks of pomegranate at small amounts.In addition to the alkaloids that build up in root and stem barks of the plant, N-(2′,5′-dihydroxyphenyl) pyridinium chloride has been identified in pomegranate leaves, and a pyrrolidine-type alkaloid punigratane (2,5-diheptyl-N-methylpyrrolidine) has been recently characterized in pomegranate fruit peel (22).

Pomegranate in Iran and ancient Persia
Pomegranate production and exports from Iran rank among the highest in the world (71).Pomegranate, known as "Anar" in Persian, grows widely and is cultivated throughout Iran.As a common food, Iranians use pomegranate fruit juice and paste in many dishes including sour chicken, Fesenjan, and Lavashak.Iranian culture has long used the pomegranate as a symbol.For instance, Isfandiyar, a legendary Persian warrior, gains invincibility by eating a pomegranate.The Persian phalanx's spears were decorated with golden pomegranates, according to Herodotus' "The Persian War." (72).Interestingly, the blossom of pomegranate (Golnar and Gole-e-anar) is the symbol of peace, love, and kindness in Iranian culture.In a Persian Achaemenid limestone bas-relief (Figure 2), a flower can be seen in the hand of the king (maybe Darius I or Xerxes) as a symbol of peace.It is interesting to note that the blossom of P. granatum var.pleniflora (Golnar-e Farsi) is known as Golnar and the flowers of other varieties are called Gole-e-anar.Persian Golnar is a plant that is grown for ornamentation and produces unproductive blossoms (Figure 3).

Pomegranate in Islamic Traditional Medicine (ITM)
Two kinds of pomegranates are described in ITM textbooks namely wild and cultivated ones with two distinct tastes sweet and sour (12).However, some ITM scientists believed that there are four tastes: astringent (un-ripped pomegranate), sweet, sour, and sour-sweet.Pomegranate's temperament differs by its type; the sweet one is cold and moist in the first degree, and the sour type is cold and dry in the second degree.The sour-sweet pomegranates, tend to be moderately dry and cold (for more information about the humors you can see Bone and Mills (73)).Sweet pomegranate is good for cold people because it makes their stomachs warm, but harmful for people with acute fever.Sour-sweet pomegranates are good for people with moderate temperament.
From a traditional point of view, pomegranate, as a low-calorie fruit, is generally an astringent, drying, and cooling agent.The most reported medicinal activities for pomegranate are attributed to its astringent property that stimulates the contraction of bodily tissues; often used to soothe the skin and stop bleeding.All types of pomegranates are astringent, however, depending on the types (sweet, sour, and sour-sweet), the benefit of each is according to the prevailing taste (14,19).It is believed that the astringency and drying properties of the pomegranate seeds are more than the juice and of the peel more than both and interestingly of the un-blossomed flowers (that fall from the trees) much more than all the latter (19).The pomegranate seed is more drying than its juice, but the peel and fleshy mesocarp are more drying than the seed.The drying power of the flower of pomegranate (known as Golnar in Persian) is like peel and fleshy mesocarp.Golnar is used as a highly astringent agent in many traditional prescriptions such as treatment of the wounds (14,17,19).Moreover, the astringency property of all parts of sour pomegranate is more than the sweet ones (19,74).A point that should be considered is that when talking about the seeds of pomegranate (known as Nardoon in Persian) in ITM, it means the sun-dried seeds with the arils not the seeds as a waste or byproduct (12-15, 19, 74-76).
Interestingly, almost all parts of the pomegranate, including, fruits, seeds, peel, leaves, bark, root, flowers (ripped and un-ripped), and even the calyx and stamens (pomegranate's crown) are used medicinally in ITM.In the following paragraphs, all the mentioned medicinal applications of pomegranate in major ITM textbooks will be discussed briefly and its applications in modern medicine will be cited in detail.

Gastrointestinal system
Pomegranate is believed to be useful for stomach and intestines (17,18,74).In some ITM textbooks, it is mentioned that while sweet pomegranate has beneficial effects on the digestive system, sour pomegranate is harmful to the stomach and scrapes the bowels.Therefore, it should be eaten with sweeteners like Halva Ardeh (a kind of Iranian sweet made of sesame and sugar) or honey (13,15).Avicenna also believed that while the sweet and soursweet pomegranates are useful for the stomach, the sour one is not good.He emphasized that the benefits of sweet pomegranate for the stomach are even more than apples and quince (17).In Menhaj: if old people want to eat a sour pomegranate, they should mix it with Balang jam (a kind of jam made from the peel of Citrus medica) (15).Al-Aghraz: both sweet and sour pomegranates are described to remove stomach heat; however sweet pomegranate is useful for the stomach and sour one is harmful (18).On the contrary, in many ITM textbooks such as Al-Jamee, sour pomegranate is also described to have beneficial effects for inflamed stomachs (14).Al-Jamee: both sour and sweet pomegranates if extracted along with their fleshy mesocarp and mixed with red sugar are stomach-strengthening agents (14).The probable point is that in Al-Jamee, sour pomegranate is prescribed with its mesocarp which has astringent properties, so it would tan the stomach.Also, Hakim Mohammad Momen Tonekaboni believed that the extract of both sweet and sour pomegranates along with their fleshy mesocarp would strengthen the stomach (75).
Razi believed that if the seeds of sour pomegranate (sundried seeds) are used in food, it would prevent the flow of excess humors to the stomach and intestines (14,19).And elsewhere in his book, it is said that pomegranate juice has the property of preventing the flow of wastes into the stomach and intestines.It is also useful for treating a fever that causes diarrhea.
In many of the studied references, an anti-parasitic activity is described for pomegranate (18,75).Razi in his book Al-Hawi has mentioned: "Pomegranate root skin when cooked with rock candy is useful for treating abdominal worms and removing Taenia eggs" (19).Ibn Beytar in his book Al-Jamee Le-Mofradaat al-Adwiah wal-Aghḏiyah (Comprehensive book in Simple Drugs and Foods): Administration of pomegranate peel in patients with intestinal worms and drinking high-temperature water after that would remove the parasites (14).Hakim Mohammad Momen Tonekaboni also believed that the administration of a drink prepared from the milled pomegranate skin in warm water is a certain cure for patients with intestinal worms (14,75).
In many ITM textbooks, the beneficial properties of pomegranate for healing intestinal wounds, its anti-diarrhea, and its stomach-strengthening activities are mentioned.It has been written in Al-Hawi that edible use of pomegranate calyx, tends to tan the stomach and dry digestive wounds (19).Purging an infusion prepared from pomegranate in combination with Oryza sativa (rice) and barley to the digestive tract has been prescribed for the treatment of diarrhea and intestinal wounds (14,75).Sitting in a bowl containing an infusion of pomegranate is also recommended for healing intestinal wounds, particularly wounds in the lower parts of the intestines (19).Golnar is also mentioned to be useful for treating these kinds of wounds.Pomegranate seed extract, especially sour pomegranate, has been used for anal wounds and hemorrhoids when cooked with honey (19).If a peeled sour pomegranate along with its mesocarp is milled in a stone mortar and squeezed, then half of the obtained extract is mixed with 10 parts of red sugar and applied, it might cause laxative effects (15).The oral use of sour pomegranate is useful for bile diarrhea and nausea (19).Roasted pomegranate seed flour is a stomach-strengthening and anti-diarrhea agent (19).Pomegranate paste also strengthens the stomach by tanning it (19).Administration of 17-25 pills (pepper seed size) prepared from the skin of sour pomegranate cooked with concentrated vinegar would heal diarrhea, and stomach, intestinal, and anal wounds (14,75).Administration of a mixture prepared of three to seven unripe pomegranate buds, some acacia leaf, and a little white cumin (milled in a stone mortar) for three to seven consecutive days would heal infants and children with diarrhea (the number of pomegranate buds depends on the child's temperament, age, and physical strength) (13).In addition, preparation was made from the flowers of pomegranate for the improvement of hernia (19).

Precautions
The sweet pomegranate produces little heat and flatus so it is not recommended for people with a warm temperament like people with acute fever (19).Razi in his book (Eliminating the Harms of Foods): "Sweet pomegranates cause a bit of bloating.Eating after a meal will lower the food from the stomach and need no adjustment because the bloating will quickly subside.But sour pomegranates have a longer stopping time in the stomach, causing bloating and severely cooling the liver, especially if used continuously.It is more harmful to cold people because it cools their liver and prevents the liver from absorbing food and thereby causes diarrhea".

In other countries
Chinese and Mexican populations have historically used pomegranate exocarp to cure gastrointestinal conditions like diarrhea, dysentery, and stomachaches (77,78).The antidiarrheal activities of punicalagin, corilagin, and ellagic acid (found in ethyl acetate fraction) alone or in combination have been confirmed (78).In India, fruit juice is traditionally used to treat dysentery by mixing it with warm water twice daily and giving it to anemic people as a tonic.Ash produced by burning seeds has a styptic quality.Fruits are consumed in their natural form to treat jaundice and strengthen the heart.Bark powder is used as an astringent with a spoonful (79).Moreover, fruit is a good source of iron in Pakistan.The fruit of the plant is consumed to treat iron deficiency.Its bark is used to treat nasal congestion.When the fruit's epicarp is dried, it is administered to cattle to cure diarrhea (80).Traditional Thai herbal medicine for treating diarrhea or bloody mucous diarrhea contains pomegranate pericarp.Studies were conducted on the formulation's antibacterial activity against microorganisms known to cause diarrhea, such as Staphylococcus aureus, Vibrio cholera, and Vibrio parahaemolyticus.Except for V. cholera, all of the bacterial pathogens examined demonstrated inhibitory zones (6.3-14.8mm) in response to the P. granatum extracts (ethanol and water) (81).

Evidence from modern medicine (Gastrointestinal system)
Decoctions and extracts from different parts of P. granatum fruit have been shown to alleviate gastrointestinal diseases such as diarrhea, gastrointestinal tumors, gastrointestinal infections such as infections caused by Helicobacter pylori, and inflammatory disorders.The studies consisted of in vitro, in vivo, and clinical studies (Table 2).

Despite promising pharmacological activities observed in
preclinical studies, there are still very few human clinical trials that study these effects.Hence, to thoroughly explore the benefits of pomegranate derivatives on the human gastrointestinal system and their safety, further clinical trials need to be done.

Respiratory system
Sweet pomegranate is useful for chronic coughing, the roughness of the throat, and chest pain and acts like a mucus-softening agent (12, 14-16, 19, 76).It is mentioned in Al-Hawi that when soaked in alum and rainwater, pomegranate is useful for the throat and lungs (19).Also, Avicenna believed when pomegranate seeds are mixed with rain water, it would be beneficial for the lower respiratory system (17).Studying the Islamic traditional textbooks showed that pomegranate is highly recommended for dry coughing (16).For instance, Ibn Beytar prescribed a mixture of pomegranate with the oil of sweet violet (Viola odorata) for dry cough (14).This beneficial effect is also mentioned by many other ITM physicians like Ibn Nafis Qarshi (16), Dawoud Antaki (12), and Ghasani (76).On the other hand, sour pomegranate is harmful to the respiratory system and it hurts the lungs and throat (15).
There is a tried prescription in several ITM textbooks for the treatment of chronic and dry coughing: "It would be a certain cure for chest pain and coughing when the pomegranate's head is pierced and repeatedly filled with sweet almond or viola oil (to the extent its capacity allows), then put on the fire to absorb the oil; drinking the obtained extract would completely remove coughing".It is also mentioned that drinking PJ with sugar, starch, Arabic gum, and almond oil has the same effect (13,14,74,75).

Evidence from modern medicine (respiratory system)
Different preparations from P. granatum and their major components such as EGCG have been reported to reduce the severity of respiratory system problems (Table 3).Some studies have evaluated the efficacy of P. granatum during the recent pandemic (101).In recent years, P. granatum fruit has been used to treat and prevent a variety of respiratory illnesses.Pomegranate fruit, juice, extract, peel powder, and oil have been shown in in vitro and in vivo studies to have positive effects on a variety of respiratory conditions, including asthma, lung fibrosis, lung cancer, chronic obstructive pulmonary disease (COPD), and alveolar inflammation by modulating a number of different mechanisms, including anti-proliferative, anti-oxidant, anti-microbial, anti-viral, anti-inflammatory, anti-cancer, and anti-tumorigenic effects.Nevertheless, pomegranate has been used in a limited number of clinical trials as an intervention for various respiratory disorders (4).Consequently, to confirm the efficacy of this natural fruit for the prevention and treatment of lung-related disorders, either alone or in combination with other medicines, welldesigned human clinical studies are advised.

Skin and wound healing properties
One of the most mentioned properties of pomegranates in ITM textbooks is their wound-healing activity (12).Since the flowers, buds, and calyx of pomegranates are the most astringent parts, administration of them has been strongly recommended for the treatment of wounds and injuries, as well as removing scars.However, other pomegranate parts and preparations such as its juice and peels have also been used for this purpose.Razi in his book Al-Hawi has mentioned: "Due to its highly astringent, drying and cooling properties, Golnar when applied to wounds or scratches, quickly heals ulcers and blocks bleeding" (19).Administration of an ointment prepared by grinding pomegranate flowers or buds and mixing them with honey  (14).In many textbooks, the burned flower or calyx has been mentioned to have such activity (15)(16)(17).Moreover, sweet pomegranate extract benefits wounds and infections when cooked in a copper dish (14).
Pomegranate has also been prescribed for other skin problems such as paronychia, scabies, thrush, erysipelas, and pruritus (12-14, 16, 75).For instance, both sour and sweet pomegranate juice along with their fleshy mesocarp concentrated in a copper pot have been prescribed for treating paronychia and scabies (75).

Evidence from modern medicine (Skin and wound)
Pomegranate is known to minimize photoaging and chronological skin aging by different anti-oxidant and antiinflammatory mechanisms.These effects are mainly due to the presence of potent polyphenols (ellagitannins and ellagic acid) (115).Pomegranate also has presented four effects considered important to the treatment of skin and soft tissue infections (antimicrobial, anti-oxidant, antiinflammatory, and healing) (116).Pomegranate whole fruit is considered to have protective activity against chemicalinduced and ultraviolet (UV) radiation-mediated cutaneous damage, including carcinogenesis (117).
The studies that have been done on this topic consist of in vitro, in vivo, and clinical studies (Table 4).These studies mostly show anti-aging, UV radiation protection, wound healing, and skin-lightening effects of pomegranate extracts.Most of the clinical studies have been conducted on the anti-aging effect of this plant's extracts, and they concluded that pomegranate extracts can alleviate the skin aging process in humans.

Reproductive system
It is believed that sour pomegranate because of its cold and dry temperament may decrease the libido and the production of semen so it is better to be served with agents with a hot temperament like ginger jam, strong wine, and Shorba (a kind of soup containing garlic and aromatic spices) (74,75).
Administration of pomegranate preparations such as its juice and paste has been repeatedly prescribed in ITM for decreasing nausea during pregnancy.Tonekaboni has mentioned in his book Tohfah: "Eating the flour obtained from dried seeds of pomegranate is useful for pregnant women who are willing to eat soil and mud" (75).
Pomegranate is believed to be useful for treating uterine wounds, infections, and inflammations (14,19).Ibn Beytar has written in Al-Jamee: "Using a purged extract obtained from boiled PJ in combination with dill would heal the chronic infections in the uterine (14).He also added that sitting in a decoction from pomegranate peels has the same activity (14).And Razi said in Al-Hawi: "Sitting in a Table 4. Therapeutic potential of Punica granatum on skin and wound Therapeutic uses of pomegranate in traditional medicine Mohammadi et al.
decoction prepared from the seeds of sour pomegranate is useful for the treatment of infections and inflammations in women's reproductive system" (19).There is also a similar healing property for the flowers of pomegranate (Golnar) (19).Pomegranate peel, due to its astringency and drying properties, benefits women with extra bleeding in their menstrual period.Tonekaboni prescribed sitting in a decoction of pomegranate peels in these circumstances (75).

Evidence from modern medicine
One of the main mechanisms of action for pomegranate against diseases related to the reproductive system is anti-oxidant activity.Age-related sexual dysfunctions are exacerbated by etiological variables such as organ damage, degenerative illnesses, and the strains of modern life.According to studies, pomegranate can reduce ROS activity in the testis and other organs.Sperms' plasma membrane is mostly composed of unsaturated fatty acids.It is hence especially vulnerable to oxidative damage.Spermatozoa membranes' lipid matrix is destroyed by lipid peroxidation, which is also linked to impairments in membrane integrity and loss of motility (139).Thus, pomegranate and its derivatives can inhibit free radicals via their anti-oxidant activities (140), improve sexual dysfunctions, and ameliorate oxidative stress and aging-induced related damages (Table 5).According to Table 5, most of these studies were in vivo and there is a need for more clinical studies to survey the effects of P. granatum and its derivatives on the reproductive system.

Mouth and teeth
Again, because of its drying and astringent properties, pomegranate (particularly its flowers) has had traditional applications for mouth and teeth problems such as repairing loose teeth, oral ulcers, toothache, gum bleeding, and improving gum health (14,19,75,76).A mouthwash from Golnar has been used to stop bleeding gums and repair loose teeth (19,75).Heravi has prescribed Golnar for the treatment of mouth ulcers and infections as well as bad breath (74).Tonekaboni even suggested PJ for the treatment of malignant mouth ulcers (75).Sour pomegranate extract is useful for infectious mouth ulcers (14).Pomegranate seed extract, especially sour pomegranate, has been used for oral wounds when cooked with honey (19).Keeping PJ in the mouth has been used to strengthen the gums and heal malignant mouth ulcers (75).Interestingly, Heravi believed that pomegranate blunts the tooth because of its astringent properties, and added that sour pomegranate destroys the Continued Table 4.

Evidence from modern medicine (mouth and teeth)
The efficacy of pomegranate has been evaluated for the treatment of mouth and teeth problems.The studies show that pomegranate is effective for a range of mouth and teeth diseases such as aphthae and chronic periodontitis (149).Mouthwash containing pomegranate extract may help prevent dental plaque and tartar buildup by stifling the activity of the bacteria that produce plaque and reducing their capacity to cling to the tooth structure.In addition to reducing oxidative stress in the oral cavity, flavonoids, one of the active components of pomegranates, are thought to prevent gingivitis through a variety of other processes (150).
The anti-microbial activities of pomegranate have been confirmed by several in vitro, animal, and clinical studies.For instance, in a study, pomegranate has shown interferences with biofilm formation against antibiotic-resistant bacterial strains and quorum sensing among biofilm microorganisms (151).Studies have revealed that pomegranate is effective against a wide range of oral pathogens including, Streptococcus salivarius, S. sanguis, S. mitis, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Prevotella intermedia (151).
In a study on the effectiveness of Achyranthes aspera, 0.2% aqueous chlorhexidine gluconate, and P. granatum mouthwashes on salivary S. mutans count in children, chlorhexidine showed better results than the other two.However, all showed a statistically significant reduction of S. mutans count and plaque index after 7 days (152).However, in another RCT on thirty children aged 6-12 years old, the activity of PPE was investigated against this pathogen and no statistically significant difference was observed between PPE and chlorhexidine as a positive control (Table 6).

Eyes, ears, and nose
Administration of a mixture of concentrated PJ, particularly sour pomegranate, with honey has been used for earache and deep nasal wounds (19,75).Ibn-e-Jazlah has prescribed a mixture of sweet PJ with honey for earache and sour one for treating pterygium (15).Ibn Beytar and Tonekaboni believed that the administration of eardrop prepared by mixing pomegranate with rose oil (Rosa damascene) would heal the earache (14,75).
ITM scientists did benefit from pomegranate for the treatment of eye problems.Antaki has mentioned: "Concentrated PJ (by the sun or by heating in a copper pan) sharpens the eyesight and is useful for the treatment of epiphora and pannus" (12).Some ancient scholars believed that eating three pomegranate calyxes protects the eye from conjunctivitis for up to a year.If the sweet PJ is put in a glass container (Gharooreh) in front of the sun to make it thick and then applied in the form of kohl (a traditional kind of mascara), it would improve the vision; the older the mixture becomes, the better it yields result (19).

Evidence from modern medicine (Eyes, ears, and nose)
Both in vitro and in vivo studies on P. granatum have indicated the protective effect of multiple preparations of this plant on retinal cell injury and ototoxicity (Table 7).However, the scope and variety of studies on this aspect are limited and clinical trials are lacking.Thus, further studies on pomegranate activities, particularly its anti-oxidant properties that have the ability to diminish or reverse agerelated ocular degeneration, are needed.

Metabolic disorders
In ITM textbooks, it has been widely emphasized that pomegranates are useful for the treatment of metabolic diseases (13,75).It is mentioned in many books that PJ imparts a rosy-colored appearance to the face (12,13,75), implying its beneficial effects on the metabolic system.The effects of pomegranate on metabolic disorders can be tracked in two main organs discussed in the following paragraphs.In our previous publication, the beneficial effects of pomegranate on different components of metabolic disorders were thoroughly discussed (9).

Liver
ITM scientists claim that pomegranate is a cooling agent for the liver (12,14,74) so it can decrease the extra heat in this organ in pathogenic conditions (14).For instance, PJ has been recommended for removing the harmful effects of alcohol from the liver.Pomegranate is claimed to act as an antidote for alcohol-induced hepatotoxicity (14,19).Many ITM researchers have mentioned that pomegranate can remove the heat in the liver caused by eating too much wine (19).However, pomegranates should be used with caution in people with cold temperaments (14).In addition, all types of pomegranate have been prescribed for treating jaundice (12).

Evidence from modern medicine
Studies (in vitro and in vivo) have revealed that pomegranate extracts from the peels, flowers, juice, and seeds can control lipid metabolism in metabolic disorderrelated illnesses like atherosclerosis, nonalcoholic fatty liver disease, and type 2 diabetes, preventing the onset of these conditions (9,169).For instance, in high-fat-fed rats, pomegranate vinegar may control lipid metabolism and lessen liver damage (170).
The beneficial activities of pomegranate extracts and preparations have been evaluated in a range of liver-related disorders.As an example, an alcoholic extract from the flowers of P. granatum has been found to abrogate ferric nitrilotriacetate-induced hepatotoxicity in mice (171).PPE may stop liver fibrosis in biliary-obstructed rats by reducing oxidative stress or increasing endogenous anti-oxidant levels (172).Pomegranate extract has also shown protective effects such as lowering triglyceride and cholesterol content of cells, normalizing the expression of pro-inflammatory  In addition, different nanoformulations have been engineered for improving the activity of pomegranate on liver disorders.For example, silver nanoparticles biosynthesized using P. granatum leaves have shown improved antidiabetic potential in vitro (173).Through boosting fatty acid consumption in hepatocytes, pomegranate-derived omega-5 nanoemulsion might reduce hepatic steatosis in mice fed a high-fat diet (174).

Heart and cardiovascular system
In ITM, pomegranate (especially sour ones) has been described as a hematopoietic (14,19), anti-palpitation (14,15,17,18,75), and vasodilatory agent (12,17,19,74).Avicenna in his book Cardiac Medications: "All types of pomegranates including, sour, sweet, and sour-sweet ones are useful for the treatment of palpitation".It is written in Al-Hawi and many other ITM textbooks that sour pomegranate acts like a polish for the heart and has the ability to burnish the cardiovascular system (14-16, 19, 76); accordingly, it can be deduced that pomegranate has anti-atherosclerosis activity (17,(74)(75)(76).Sour pomegranate prevents the flow of waste materials to the body (15) and quenches the excitation of yellow bile, black bile, and blood humor (14,74,75).Razi in Al-Hawi has mentioned: The pomegranate paste particularly the one concentrated in a copper pan is used to remove the excess amount of these humors (19).

Evidence from modern medicine
Pomegranate and its derivatives have been found to have protective effects on the cardiovascular system, according to several in vivo and clinical investigations.These vasculoprotective actions include lowering oxidative stress, improving macrophage, endothelial cell, and platelet function, decreasing blood glucose levels, lowering lipid oxidation, and having vasodilatory effects in addition to lowering blood pressure by inhibiting ACE activity (175).For instance, P. granatum flower extract could diminish cardiac fibrosis in Zucker diabetic fatty rats by modulation of cardiac endothelin-1 and NF-κB pathways (176).It could also protect isoproterenol-treated rats against myocardial damage by acting as a free radical scavenger and conserving the endogenous anti-oxidant system (177).A study showed how pomegranate, prickly pear, and apple juice vinegar can protect against swelling, hypertrophy, and fibrosis in obesity-related heart damage (178).Moreover, in individuals with unstable angina, PJ may lessen the frequency, onset, and length of angina pectoris attacks (179).In addition, according to the literature, pomegranate has the ability to reduce blood pressure.For example, the data from a metaanalysis evaluating 8 RCTs showed that PJ can significantly decrease both systolic and diastolic blood pressure levels (180).

Other traditional systems of medicine around the world
Table 8 shows the medicinal application of pomegranate in different countries around the world.Most of the usages mentioned in the table are similar to the prescriptions in ITM textbooks showing the knowledge transfer from Persia to other parts of the world.Similarly, different preparations from all parts of pomegranate including leaves, seeds, fruits, and peels are mentioned.Pomegranate is a well-known medicinal plant in Indian traditional systems of medicine including Ayurveda and Unani medicine.

Conclusion
Pomegranate fruits, leaves, blossoms, and seeds have all been used to cure several ailments in Persian and Islamic traditional medicines.However, pomegranate fruit juice and peel have received far more attention than the other parts.By comparing the ITM findings to modern medical evidence, we can deduce that a significant part of ITM findings is confirmed by modern medicine (195)(196)(197).For instance, the anti-bacterial activity of pomegranate in treating wounds, and infections such as respiratory, mouth, teeth, gastrointestinal, and uterine infections were well established in ITM books.Another instance of this conformity is the anti-oxidant property of pomegranate which is useful in the treatment of inflammation, skin aging, atherosclerosis, and metabolic disorders.
Though some of these traditional medical practices have been studied by modern medicine, many are still in their very early stages to be investigated.Although the main bioactive constituents of pomegranate preparations are polyphenols, there are yet insufficient data on the identification and isolation of the bioactive chemicals that are responsible  for the biological activities.In addition, more preclinical and clinical research is demanded to confirm the other traditional applications, find the mechanisms of action, and evaluate the efficacy and safety.Overall, the potential of this valuable fruit and functional food can be fully realized via examination of the variety and interrelation of pomegranate phytochemicals as well as preclinical and clinical studies of their bioactivities.

1
Pomegranate peel extract; 2 Pomegranate juice Therapeutic uses of pomegranate in traditional medicine Mohammadi et al.

Table 3 .1
Therapeutic potential of Punica granatum on the respiratory system 21 Pomegranate peel extract; 2 Epigallocatechin Gallate; 3 Pomegranate juice on smallpox scars and other wounds for several consecutive days would eliminate the scars

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Therapeutic uses of pomegranate in traditional medicineMohammadi et al.
improving mitochondrial complex activity in obesity-associated nonalcoholic fatty liver disease (1).

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Therapeutic uses of pomegranate in traditional medicineMohammadi et al.

1 2 3 Table 1 .
Some of the main phytochemicals reported from Punica granatum Iran J Basic Med Sci, 2023, Vol. 26, No. 11Therapeutic uses of pomegranate in traditional medicineMohammadi et al.Continued

Table 2 .
Therapeutic potential of Punica granatum on the gastrointestinal system

Table 5 .
Therapeutic potential of Punica granatum on the reproductive system

Table 6 .
Therapeutic potential of Punica granatum on mouth and teeth

Table 7 .
Therapeutic potential of Punica granatum on eyes, ears, and nose 28